The invention relates to modulation of nitric oxide (NO) to treat epidermal and dermal conditions.
Organic nitrates and their gaseous metabolic end-product, nitric oxide (NO), have been implicated to date in a vast array of biologically diverse activities (Snyder et al. (1992) Sci Amer 5:68-77). The growth in interest in the biological effects of NO began in 1980 when it was noticed that relaxation of blood vessels (vasodilatation) no longer occurred when the endothelial layer was stripped from the vessels. The molecule mediating this effect was termed endothelial-derived-relaxing-factor (EDRF). In 1987, EDRF was shown to be nitric oxide (NO).
Three nitric oxide synthase (NOS) isoforms have been characterized. A constitutive form is found in neuronal cells (nNOS) (Schmidt et al. (1991) Biochem Biophys Res Comm 181:1372-77), an inducible form (iNOS) is found in macrophages (Xie et al. (1992) Science 256:225-28; Lyons et al. (1992) J Bio Chem 267:6370-74), while another constitutive form is produced by endothelial cells (eNOS) (Janssens et al. (1992) J Biol Chem 267:14519-22). These are also known as Types I, II and III, respectively (Pollock et al. (1991) Proc Natl Acad Sci USA 88:10480-84).
The role of NO in the vascular system has been shown to be extensive (Vane et al. (1990) New Eng J Med 323:27-36). NO participates in the regulation of systemic blood pressure as evidenced by hypertension in mice in which the eNOS gene has been knocked out by homologous recombination (Huang et al. (1995) Nature 377:239-42). Decreasd responsiveness to NO in the pulmonary vasculature contributes to pulmonary hypertension while the vasodilator effects of NO are necessary for penile erection (Saenz et al. (1989) New Eng J Med 320:1025-30). Cutaneous vasculature has received some attention because the dermis has an extensive capillary network and these capillaries serve as a good model to study microcirculation in man. As in other blood vessels, the endothelium lining the dermal capillaries expresses eNOS. It has been observed that in the presence of NO, blood flow in the human skin microcirculation is remarkably increased and in the presence of inhibitors of NOS, vasodilatation is impaired (Warren, JB (1994) FASEB J 8:247-51; Ralevic et al. (1992) Br J Pharmacol 106:650-655).
Large amounts of NO are produced when macrophages are cultured with interferon-gamma (IFN-.gamma.), tumor necrosis factor-alpha (TNF-.alpha.) or low doses of lipopolysaccharide (LPS) (Stuehr et al. (1985) Proc Natl Acad Sci USA 82:7738-42). Production of NO by macrophages is toxic to bacteria and parasites (Liew et al. (1991) Immunol Today 12(3):A17-A21). For example, resistance of mice to Leishmania major infection correlates with the induction of NOS in macrophages (Liew et al. (1990) J Immunol 144:4794-97). In mice where the iNOS gene has been knocked out, leishmania infection is severe.
The fact that NO is a neuronal messenger was first appreciated when it was shown that cerebellar granule cells release NO after exposure to glutamate agonists (Garthwaite, J. (1991) Trends Neurosci 14:60-67). NOS containing neurons are found throughout the central and peripheral nervous systems (Bredt et al. (1992) Neuron 8:3-11). NO plays a key role in nervous system morphogenesis and synaptic plasticity.